Burst Firing In Thalamocortical Neurons Research Articles

Clinical and experimental insight into pathophysiology, comorbidity and therapy of absence seizures.

Absence seizures in children and teenagers are generally considered relatively benign because of their non-convulsive nature and the large incidence of remittance in early adulthood. Recent studies, however, show that 30% of children with absence seizures are pharmaco-resistant and 60% are affected by severe neuropsychiatric comorbid conditions, including impairments in attention, cognition, memory and mood. In particular, attention deficits can be detected before the epilepsy diagnosis, may persist even when seizures are pharmacologically controlled and are aggravated by valproic acid monotherapy. New functional MRI-magnetoencephalography and functional MRI-EEG studies provide conclusive evidence that changes in blood oxygenation level-dependent signal amplitude and frequency in children with absence seizures can be detected in specific cortical networks at least 1 min before the start of a seizure, spike-wave discharges are not generalized at seizure onset and abnormal cortical network states remain during interictal periods. From a neurobiological perspective, recent electrical recordings and imaging of large neuronal ensembles with single-cell resolution in non-anaesthetized models show that, in contrast to the predominant opinion, cortical mechanisms, rather than an exclusively thalamic rhythmogenesis, are key in driving seizure ictogenesis and determining spike-wave frequency. Though synchronous ictal firing characterizes cortical and thalamic activity at the population level, individual cortico-thalamic and thalamocortical neurons are sparsely recruited to successive seizures and consecutive paroxysmal cycles within a seizure. New evidence strengthens previous findings on the essential role for basal ganglia networks in absence seizures, in particular the ictal increase in firing of substantia nigra GABAergic neurons. Thus, a key feature of thalamic ictogenesis is the powerful increase in the inhibition of thalamocortical neurons that originates at least from two sources, substantia nigra and thalamic reticular nucleus. This undoubtedly provides a major contribution to the ictal decrease in total firing and the ictal increase of T-type calcium channel-mediated burst firing of thalamocortical neurons, though the latter is not essential for seizure expression. Moreover, in some children and animal models with absence seizures, the ictal increase in thalamic inhibition is enhanced by the loss-of-function of the astrocytic GABA transporter GAT-1 that does not necessarily derive from a mutation in its gene. Together, these novel clinical and experimental findings bring about paradigm-shifting views of our understanding of absence seizures and demand careful choice of initial monotherapy and continuous neuropsychiatric evaluation of affected children. These issues are discussed here to focus future clinical and experimental research and help to identify novel therapeutic targets for treating both absence seizures and their comorbidities.

Brain stimulation patterns emulating endogenous thalamocortical input to parvalbumin-expressing interneurons reduce nociception in mice

BackgroundThe bursting pattern of thalamocortical (TC) pathway dampens nociception. Whether brain stimulation mimicking endogenous patterns can engage similar sensory gating processes in the cortex and reduce nociceptive behaviors remains uninvestigated. ObjectiveWe investigated the role of cortical parvalbumin expressing (PV) interneurons within the TC circuit in gating nociception and their selective response to TC burst patterns. We then tested if transcranial magnetic stimulation (TMS) patterned on endogenous nociceptive TC bursting modulate nociceptive behaviors. MethodsThe switching of TC neurons between tonic (single spike) and burst (high frequency spikes) firing modes may be a critical component in modulating nociceptive signals. Deep brain electrical stimulation of TC neurons and immunohistochemistry were used to examine the differential influence of each firing mode on cortical PV interneuron activity. Optogenetic stimulation of cortical PV interneurons assessed a direct role in nociceptive modulation. A new TMS protocol mimicking thalamic burst firing patterns, contrasted with conventional continuous and intermittent theta burst protocols, tested if TMS patterned on endogenous TC activity reduces nociceptive behaviors in mice. ResultsImmunohistochemical evidence confirmed that burst, but not tonic, deep brain stimulation of TC neurons increased the activity of PV interneurons in the cortex. Both optogenetic activation of PV interneurons and TMS protocol mimicking thalamic burst reduced nociceptive behaviors. ConclusionsOur findings suggest that burst firing of TC neurons recruits PV interneurons in the cortex to reduce nociceptive behaviors and that neuromodulation mimicking thalamic burst firing may be useful for modulating nociception.

The interplay of seven subthreshold conductances controls the resting membrane potential and the oscillatory behavior of thalamocortical neurons.

The signaling properties of thalamocortical (TC) neurons depend on the diversity of ion conductance mechanisms that underlie their rich membrane behavior at subthreshold potentials. Using patch-clamp recordings of TC neurons in brain slices from mice and a realistic conductance-based computational model, we characterized seven subthreshold ion currents of TC neurons and quantified their individual contributions to the total steady-state conductance at levels below tonic firing threshold. We then used the TC neuron model to show that the resting membrane potential results from the interplay of several inward and outward currents over a background provided by the potassium and sodium leak currents. The steady-state conductances of depolarizing Ih (hyperpolarization-activated cationic current), IT (low-threshold calcium current), and INaP (persistent sodium current) move the membrane potential away from the reversal potential of the leak conductances. This depolarization is counteracted in turn by the hyperpolarizing steady-state current of IA (fast transient A-type potassium current) and IKir (inwardly rectifying potassium current). Using the computational model, we have shown that single parameter variations compatible with physiological or pathological modulation promote burst firing periodicity. The balance between three amplifying variables (activation of IT, activation of INaP, and activation of IKir) and three recovering variables (inactivation of IT, activation of IA, and activation of Ih) determines the propensity, or lack thereof, of repetitive burst firing of TC neurons. We also have determined the specific roles that each of these variables have during the intrinsic oscillation.

Sleep spindles are generated in the absence of T-type calcium channel-mediated low-threshold burst firing of thalamocortical neurons

T-type Ca(2+) channels in thalamocortical (TC) neurons have long been considered to play a critical role in the genesis of sleep spindles, one of several TC oscillations. A classical model for TC oscillations states that reciprocal interaction between synaptically connected GABAergic thalamic reticular nucleus (TRN) neurons and glutamatergic TC neurons generates oscillations through T-type channel-mediated low-threshold burst firings of neurons in the two nuclei. These oscillations are then transmitted from TC neurons to cortical neurons, contributing to the network of TC oscillations. Unexpectedly, however, we found that both WT and KO mice for CaV3.1, the gene for T-type Ca(2+) channels in TC neurons, exhibit typical waxing-and-waning sleep spindle waves at a similar occurrence and with similar amplitudes and episode durations during non-rapid eye movement sleep. Single-unit recording in parallel with electroencephalography in vivo confirmed a complete lack of burst firing in the mutant TC neurons. Of particular interest, the tonic spike frequency in TC neurons was significantly increased during spindle periods compared with nonspindle periods in both genotypes. In contrast, no significant change in burst firing frequency between spindle and nonspindle periods was noted in the WT mice. Furthermore, spindle-like oscillations were readily generated within intrathalamic circuits composed solely of TRN and TC neurons in vitro in both the KO mutant and WT mice. Our findings call into question the essential role of low-threshold burst firings in TC neurons and suggest that tonic firing is important for the generation and propagation of spindle oscillations in the TC circuit.

Cortical and thalamic components of neocortical kindling-induced epileptogenesis in behaving cats

Kindling is an essential operating paradigm of the nervous system extensively used both as a model of epileptogenesis and neuroplasticity. In a parallel study conducted on chronically implanted non-anesthetized kindled cats, we report the occurrence of long-lasting slow oscillatory patterns (1.5–2 Hz) called outlasting activities (OA) following the acute seizures (AS) induced by cortical stimulation. Here, we asked if OA observed in the neocortex of kindled animals are generated exclusively by the cortical networks or if they also rely on the burst firing of thalamic neurons. We analyzed the electrophysiological patterns of synchronization of cortical EEG (areas 4, 5, 7, 21, 17, 18, 22) and thalamic field (EThG) (ventral posterior lateral nucleus—VPL), and the influence of modulatory systems originating in the pedunculo-pontine tegmentum (PPT) and locus coeruleus (LC) on the discharge pattern of thalamic neurons during OA. Synchrony analysis of field recordings showed that during AS cortical paroxysmal activities preceded thalamic ones, while during OA this sequential order was reversed. During OA thalamic neurons regularly discharged bursts with the frequency of OA. Electrical stimulation of either PPT or LC during OA decreased both the probability of bursts in thalamocortical neurons and the amplitude of OA. Yet, neither of them was able to block completely the expression of OA. Following PPT/LC stimulation the burst firing of thalamocortical neurons was replaced by tonic firing. We conclude that the thalamus is involved in the mechanism of generation of OA but that it does not play an exclusive role.

Propofol block of Ih contributes to the suppression of neuronal excitability and rhythmic burst firing in thalamocortical neurons

Propofol block of <i>I</i>_h contributes to the suppression of neuronal excitability and rhythmic burst firing in thalamocortical neurons

Propofol block of Ih contributes to the suppression of neuronal excitability and rhythmic burst firing in thalamocortical neurons

Although the depressant effects of the general anesthetic propofol on thalamocortical relay neurons clearly involve gamma-aminobutyric acid (GABA)(A) receptors, other mechanisms may be involved. The hyperpolarization-activated cation current (I(h)) regulates excitability and rhythmic firing in thalamocortical relay neurons in the ventrobasal (VB) complex of the thalamus. Here we investigated the effects of propofol on I(h)-related function in vitro and in vivo. In whole-cell current-clamp recordings from VB neurons in mouse (P23-35) brain slices, propofol markedly reduced the voltage sag and low-threshold rebound excitation that are characteristic of the activation of I(h). In whole-cell voltage-clamp recordings, propofol suppressed the I(h) conductance and slowed the kinetics of activation. The block of I(h) by propofol was associated with decreased regularity and frequency of delta-oscillations in VB neurons. The principal source of the I(h) current in these neurons is the hyperpolarization-activated cyclic nucleotide-gated (HCN) type 2 channel. In human embryonic kidney (HEK)293 cells expressing recombinant mouse HCN2 channels, propofol decreased I(h) and slowed the rate of channel activation. We also investigated whether propofol might have persistent effects on thalamic excitability in the mouse. Three hours following an injection of propofol sufficient to produce loss-of-righting reflex in mice (P35), I(h) was decreased, and this was accompanied by a corresponding decrease in HCN2 and HCN4 immunoreactivity in thalamocortical neurons in vivo. These results suggest that suppression of I(h) may contribute to the inhibition of thalamocortical activity during propofol anesthesia. Longer-term effects represent a novel form of propofol-mediated regulation of I(h).

Contribution of GABAAand GABABReceptors to Thalamic Neuronal Activity during Spontaneous Absence Seizures in Rats

The contribution of GABAergic mechanisms in thalamic relay nuclei to spike and wave discharges (SWDs) during spontaneous seizures was assessed using the WAG/Rij strain of rats, an established genetic model of absence epilepsy, in combination with single-unit recordings and microiontophoretic techniques in the ventrobasal thalamic complex in vivo. Spontaneous SWDs occurring on the electroencephalogram at 5-9 Hz were associated with burst firing in thalamocortical neurons, which was phase-locked with the spike component. Microiontophoretic application of the GABA(A) receptor antagonist bicuculline significantly increased the magnitude of SWD-related firing in all tested cells. Application of the GABA(B) receptor antagonist CGP 55845A exerted a statistically insignificant modulatory effect on neuronal activity during spontaneous SWDs but significantly attenuated the bicuculline-evoked aggravation of SWD-related firing. The data indicate that, in thalamocortical neurons, (1) GABA(A) receptor-mediated events are recruited with each SWD, (2) SWD-related activity can be evoked with no significant contribution of GABA(B) receptors, and (3) blockade of GABA(A) receptors potentiates SWD-related activity, presumably through an indirect effect mediated through GABA(B) receptors. These results vote against a predominant or even exclusive contribution of GABA(B) receptors to spontaneous SWDs in thalamic relay nuclei in the WAG/Rij strain, but rather point to a critical role of GABA(A) receptor activation. This conclusion is in support of the view that the two subtypes of GABA receptors play a differential role in fast (5-10 Hz) and slow (3 Hz) spike-wave paroxysms observed during absence seizures.

Dynamic clamp study of I h modulation of burst firing and δ oscillations in thalamocortical neurons in vitro

The dynamic clamp technique was used in thalamocortical neurons of the rat and cat dorsal lateral geniculate nucleus in vitro to investigate the effects of the hyperpolarization-activated cation current, I h, and of its neuromodulation on burst firing and δ oscillations. Specific block of endogenous I h using 4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino)pyridinium chloride (ZD7288) (300 μM) abolished the depolarizing “sag” response to negative current steps, markedly increased the latency and shortened the duration of the low-threshold Ca 2+ potentials, and decreased the number of action potentials in the burst evoked by the low-threshold Ca 2+ potential. Subsequent introduction of artificial I h using the dynamic clamp re-instated the “sag” and all the original properties of the low-threshold Ca 2+ potential. In the absence of ZD7288, introduction of artificial outward I h with the intention of abolishing endogenous I h removed the depolarizing “sag” and produced similar effects on the low-threshold Ca 2+ potentials as those observed during the pharmacological block of I h. Application of ZD7288 to thalamocortical neurons displaying δ oscillations led to a reduction in the voltage range of their existence or to a complete cessation of this behaviour. A subsequent introduction of artificial I h re-enabled the generation of δ oscillations. In the presence of ZD7288, physiologically relevant positive shifts in the voltage-dependence of artificial I h increased the amplitude and duration of the low-threshold Ca 2+ potential and increased the likelihood of δ oscillations while negative shifts had opposite effects. These results highlight the important difference between the dependence of burst firing and oscillations on membrane potential and their dependence on the properties of I h, and demonstrate that the modulation by I h of low-threshold Ca 2+ potentials and burst firing in thalamocortical neurons, as well as the ability of these neurons to generate δ oscillations, is more elaborate than previously described.

Gamma-hydroxybutyrate promotes oscillatory activity of rat and cat thalamocortical neurons by a tonic GABAB, receptor-mediated hyperpolarization.

The actions of gamma-hydroxybutyrate, a drug known to lead to an increase in nocturnal slow wave sleep and induce epileptic states following systemic application, on the membrane properties of thalamocortical neurons from brain slices of the rat and cat dorsal lateral geniculate nucleus were studied using sharp electrode intracellular recordings. Gamma-hydroxybutyrate applied by addition to the perfusion medium led to a concentration-dependent and reversible hyperpolarization of the membrane potential accompanied by a decrease in apparent input resistance (0.1 mM: 2.3 +/- 0.3 mV, 9.5 +/- 1.0%; 10 mM: 11.3 +/- 1.3 mV, 37.5 +/- 10.8%, respectively). In six of seven neurons the iontophoretic or bath (0.1-0.2 mM) application of low concentrations of gamma-hydroxybutyrate led to a hyperpolarization accompanied by the appearance of low-frequency (< 4 Hz) membrane potential oscillations crowned by bursts of action potentials, when the membrane potential of these neurons was initially set depolarized to the range where ongoing oscillatory activity occurred. The gamma-hydroxybutyrate-elicited hyperpolarization was reversibly antagonized by the co-application of the GABAB receptor antagonist CGP 35348 (0.4-1 mM), but was not affected by the putative gamma-hydroxybutyrate receptor antagonist NCS 382 (0.1-5 mM) or tetrodotoxin (1 microM), suggesting that gamma-hydroxybutyrate tonically activates postsynaptic GABAB receptors. The gamma-hydroxybutyrate-induced promotion of oscillatory activity and action potential burst firing of thalamocortical neurons may be one mechanism by which gamma-hydroxybutyrate leads to an increase in the deep stages of sleep and the generation of electroencephalogram and behavioural patterns typical of absence epilepsy.